In the literature, several works aim to improve the performance of hydrocyclones using geometry optimization. However, these approaches do not consider the uncertainties in the models, design variables, and parameters, which can lead to solutions that do not correspond to the expected results when applied to real systems. Considering that, the present work proposed a reliability-based optimization of the hydrocyclone dimensions using the Advanced Mean Value (AMV) technique associated with the Multi-Objective Differential Evolution (MODE) algorithm. For that purpose, the maximization of total efficiency and minimization of underflow-to-throughput ratio and Euler number were taken as objectives and constraints were set to ensure an acceptable performance of the hydrocyclone in the main aspects of the process. Some of the obtained devices were selected to be fabricated through an additive manufacturing technique (3D printing) and, after that, be experimentally tested. The optimization results showed that the reliability-based optimization affected the Pareto curves in two different ways: a shortening or a displacement of the curve in relation to the nominal one, depending on which constraints are being activated. The experimental results demonstrated that the hydrocyclones obtained by the reliable approach had a greater tendency to meet the set constraints in practice. Finally, hydrocyclones with great experimental performance were obtained considering separation efficiency, concentration capacity, and energy consumption.